The aging of the population and the increase of chronic metabolic diseases such as hypertension or diabetes has favored the presence of chronic ulcers in recent years.
Occasionally, due to the health condition of the patient (diabetes) or to the presence of a large amount of damage in the tissue (serious burns), phenomena can arise which alter the series of processes which must take place for healing to occur, developing a chronic ulcer.
The formation of a chronic ulcer is associated with an excessive inflammatory process which alters the synthesis of the signaling molecules involved in regulating the process taking place in healing. Recent studies directly relate the physiopathology of chronic ulcers with the oxidative stress present in the bed of the wound, as a consequence of the proinflammatory environment of the lesioned area.
When oxidative stress occurs, the organism has detoxification mechanisms capable of control the excess of the reactive oxygen species generated, in contrast, when there is a lack of adjustment between the detoxificant capacity of the organism and the free radicals present in the bed of the wound, the healing process slows down, giving rise to a chronic ulcer.
A lack of adjustment in the detoxification mechanisms of reactive oxygen metabolites is one of the main causes of chronicity in ulcers.
The healing of chronic wounds may be induced by the use of antioxidant wound dressings that react specifically with excess reactive oxygen species and hence reduce the level of oxidative stress. In the art, different examples of materials for healing purposes are described.
For example, in U.S. Pat. No. 6,406,712, a wound dressing material has been described, which is formed by mixing dry hydrocolloid polymer powder with water contained in a sealed package having a temporary or manually-removable barrier so that the dry polymer and water can be stored separately from each other while in the package.
Another description, at the patent application WO 01/49258A2, comprises tissue contact materials, such as biocompatible polymer comprising a non-gellable polysaccharide, such as guar gum, that entrap oxygen within closed cell foam-like material capable of providing or maintaining optimal oxygen tension at a compromised tissue site while absorbing excess fluid and optimizing the microenvironment to facilitate tissue repair and regeneration if needed.
The patent application EP0781550A1, describes a bioadhesive pharmaceutical composition for the controlled liberation of active ingredients, antiulcer among others, constituted by a co-polymer of vinyl acetate and polyvinylpyrrolidone and an additional component, such as the locust bean gum among others.
The antioxidant activity of galactomannans upon reducing the lipid peroxidation of systems subjected to UVA radiation has also recently been described. Their capacity to increase the elasticity of different mixtures of hydrogels and their capacity to absorb water, being able to provide the bed of the wound with the necessary degree of moisture needed by the healing process, are also known.
The international application WO2005/084650A1 claims a storage stable and dry active ingredient delivery system for pharmaceutically active ingredients for dermal use with wound healing purposes. The delivery system comprises a xerogel in that the gel-forming material is a polysaccharide, for example galactomannan derivatives. When the xerogel comes into contact with fluids it is rehydratated and forms a hydrogel, whereby the applied active ingredients are dissolved and released at a controlled rate from the hydrogel leading to a locally high concentration.
Solid, bioabsorbable materials for use as wound dressings are described at the patent application EP0792653, where such a solid is formed by a mixture of xanthan, and at least one galactomannan, such as guar gum or locust bean gum. The material also comprises therapeutic agents among which are particularly preferred those that actively promote wound healing such as glicosaminoglycans.
In a similar procedure as described above a wound dressing with healing purposes is claimed by the international application WO99/25395, where the matrix comprises a biocompatible cross-linked polymer and a non-gellable polysaccharide, a galactomannan, which includes as well one or more active ingredients, for example, wound healing agents like growth factors, mucopolysacharides and proteins.
Other types of wound healing dressings are described by the international applications WO2004/112850 and WO2005/049101 where generally the material is formed by a bioabsorbable substrate, which could be galactomannan, dyed with an antioxidant dyestuff, which can react with oxygen reactive species, reducing, in that way, the level of oxidative stress at the wound.
N-acetyl cysteine is also known as an antioxidant molecule which acts by increasing the synthesis of intracellular glutatión (GSH). The reducing effect of GSH contributes to directly eliminating the reactive oxygen species and also to recycling already used antioxidants. Its use in chronic ulcers would reduce the oxidative stress thereof, thus favoring their healing (Manikandan, P. et al, Molecular and Cellular Biochemistry, 2006, 290, 87-96; Rani Thaakur, S. et al, Pharmacologyonline, 2009, 1, 369-376).
The antioxidant activity of curcumin is also known. Curcumin is the purified state of the raw extract of Turmeric root, a plant mostly cultivated in Southeast Asia and widely used in traditional medicine for the treatment of skin-related diseases. Gopinath, D. (Biomaterials, 2004, 25, 1911-1917) demonstrates the improved capacity of wound healing by curcumin antioxidant when it is incorporated to a collagen matrix, which also acts as a supportive matrix for the regenerative tissue.
Although the antioxidant properties of galactomannans and N-acetyl cysteine are well-documented in the prior art, there is no indication about the particular advantages conferred by the combination of both components, and particularly, to the antioxidant synergistic effect provided on cells cultures suffering extensive oxidative stress.